New unique tools are emerging for malaria control and elimination. The overall aim of this proposal is to develop and test one emerging technology, tafenoquine. Tafenoquine is a new 8-aminoquinoline with transmission blocking activity against malaria. In addition, it has a highly desirable 2-3 week half-life. With these properties, interruption of falciparum malaria transmission with a single dose of drug should be possible. If so, this drug will have utility in controlling malaria epidemics and in malaria control/elimination efforts. The US Army is co-developing tafenoquine with Smith Kline Beecham for malaria prophylaxis. Public health indications that are not directly relevant to the military mission require outside funding. The chief objectives of this research plan are to complete the necessary steps towards and then to conduct "proof-of-concept" clinical trials for transmission blocking. An in vivo dose-response trial for tafenoquine's anti-gametocytocidal (anti-sexual stage) activity will be required to determine the appropriate dose. The treatment of children will be required for a transmission blocking field trial. Currently, there is no plan for a pediatric formulation or indication. Yet, children can benefit the most from this drug. With these background requirements completed, we plan to conduct a "proof-of-concept' population field trial. We believe this can be best accomplished by randomizing islands or isolated populations to active intervention or ho active intervention in an area of unstable (intermittent) malaria transmission. AIM 1. Complete the requisite steps to initiate population-based field trials with tafenoquine. 1A. Define dose-response and concentration-response relationships for transmission-blocking in Phase II clinical trials. 1B. Develop an acceptable pediatric drug formulation. 1C. Determine the safety, pharmacokinetics and efficacy of tafenoquine in children. 1D. Identify field sites and prepare for intervention trials. AIM 2. Test the hypothesis that malaria transmission can be interrupted with tafenoquine in isolated populations.